Decreased function of voltage-gated potassium channels contributes to augmented myogenic tone of uterine arteries in late pregnancy

2008 ◽  
Vol 294 (1) ◽  
pp. H272-H284 ◽  
Author(s):  
Vsevolod Telezhkin ◽  
Tara Goecks ◽  
Adrian D. Bonev ◽  
George Osol ◽  
Natalia I. Gokina
Keyword(s):  
Smooth Muscle ◽  
Smooth Muscle Cell ◽  
Late Pregnancy ◽  
Intraluminal Pressure ◽  
Delayed Rectifier ◽  
Myogenic Tone ◽  
Channel Activity ◽  
Voltage Gated ◽  
Uterine Arteries ◽  
Increased Pressure

Increased pressure-induced (myogenic) tone in small uteroplacental arteries from late pregnant (LP) rats has been previously observed. In this study, we hypothesized that this response may result from a diminished activity of vascular smooth muscle cell (SMC) voltage-gated delayed-rectifier K+ (Kv) channels, leading to membrane depolarization, augmented Ca2+ influx, and vasoconstriction (tone). Elevation of intraluminal pressure from 10 to 60 and 100 mmHg resulted in a marked, diltiazem-sensitive rise in SMC cytosolic Ca2+ concentration ([Ca2+]i) associated with a vasoconstriction of uteroplacental arteries of LP rats. In contrast, these changes were significantly diminished in uterine arteries from nonpregnant (NP) rats. Gestational augmentation of pressure-induced Ca2+ influx through L-type Ca2+ channels was associated with an enhanced SMC depolarization, the appearance of electrical and [Ca2+]i oscillatory activities, and vasomotion. Exposure of vessels from NP animals to 4-aminopyridine, which inhibits the activity of Kv channels, mimicked the effects of pregnancy by increasing pressure-induced depolarization, elevation of [Ca2+]i, and development of myogenic tone. Furthermore, currents through Kv channels were significantly reduced in myocytes dissociated from arteries of LP rats compared with those of NP controls. Based on these results, we conclude that decreased Kv channel activity contributes importantly to enhanced pressure-induced depolarization, Ca2+ entry, and increase in myogenic tone present in uteroplacental arteries from LP rats.

scholarly journals Voltage-gated Ca2+channel activity modulates smooth muscle cell calcium waves in hamster cremaster arterioles

2018 ◽  
Vol 315 (4) ◽  
pp. H871-H878 ◽  
Author(s):  
William F. Jackson ◽  
Erika M. Boerman
Keyword(s):  
Smooth Muscle ◽  
Channel Blocker ◽  
Muscle Tone ◽  
Myogenic Tone ◽  
Calcium Waves ◽  
Cremaster Muscle ◽  
Channel Activity ◽  
Voltage Gated ◽  
Inositol 1,4,5 Trisphosphate ◽  
Trisphosphate Receptor

Cremaster muscle arteriolar smooth muscle cells (SMCs) display inositol 1,4,5-trisphosphate receptor-dependent Ca2+waves that contribute to global myoplasmic Ca2+concentration and myogenic tone. However, the contribution made by voltage-gated Ca2+channels (VGCCs) to arteriolar SMC Ca2+waves is unknown. We tested the hypothesis that VGCC activity modulates SMC Ca2+waves in pressurized (80 cmH2O/59 mmHg, 34°C) hamster cremaster muscle arterioles loaded with Fluo-4 and imaged by confocal microscopy. Removal of extracellular Ca2+dilated arterioles (32 ± 3 to 45 ± 3 μm, n = 15, P < 0.05) and inhibited the occurrence, amplitude, and frequency of Ca2+waves ( n = 15, P < 0.05), indicating dependence of Ca2+waves on Ca2+influx. Blockade of VGCCs with nifedipine (1 μM) or diltiazem (10 μM) or deactivation of VGCCs by hyperpolarization of smooth muscle with the K+channel agonist cromakalim (10 μM) produced similar inhibition of Ca2+waves ( P < 0.05). Conversely, depolarization of SMCs with the K+channel blocker tetraethylammonium (1 mM) constricted arterioles from 26 ± 3 to 14 ± 2 μm ( n = 11, P < 0.05) and increased wave occurrence (9 ± 3 to 16 ± 3 waves/SMC), amplitude (1.6 ± 0.07 to 1.9 ± 0.1), and frequency (0.5 ± 0.1 to 0.9 ± 0.2 Hz, n = 10, P < 0.05), effects that were blocked by nifedipine (1 μM, P < 0.05). Similarly, the VGCC agonist Bay K8644 (5 nM) constricted arterioles from 14 ± 1 to 8 ± 1 μm and increased wave occurrence (3 ± 1 to 10 ± 1 waves/SMC) and frequency (0.2 ± 0.1 to 0.6 ± 0.1 Hz, n = 6, P < 0.05), effects that were unaltered by ryanodine (50 μM, n = 6, P > 0.05). These data support the hypothesis that Ca2+waves in arteriolar SMCs depend, in part, on the activity of VGCCs.NEW & NOTEWORTHY Arterioles that control blood flow to and within skeletal muscle depend on Ca2+influx through voltage-gated Ca2+channels and release of Ca2+from internal stores through inositol 1,4,5-trisphosphate receptors in the form of Ca2+waves to maintain pressure-induced smooth muscle tone.

Vascular smooth muscle cell stress as a determinant of cerebral artery myogenic tone

2002 ◽  
Vol 283 (6) ◽  
pp. H2210-H2216 ◽  
Author(s):  
Johan Fredrik Brekke ◽  
Natalia I. Gokina ◽  
George Osol
Keyword(s):  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Smooth Muscle Cell ◽  
Muscle Cell ◽  
Vascular Smooth Muscle Cell ◽  
Wall Stress ◽  
Cytosolic Calcium ◽  
Cell Stress ◽  
Myogenic Tone ◽  
Vessel Size

Although the level of myogenic tone (MT) varies considerably from vessel to vessel, the regulatory mechanisms through which the actual diameter set point is determined are not known. We hypothesized that a unifying principle may be the equalization of active force at the contractile filament level, which would be reflected in a normalization of wall stress or, more specifically, media stress. Branched segments of rat cerebral arteries ranging from <50 μm to >200 μm in diameter were cannulated and held at 60 mmHg with the objectives of: 1) evaluating the relationship between arterial diameter and the extent of myogenic tone, 2) determining whether differences in MT correlate with changes in cytosolic calcium ([Ca2+]i), and 3) testing the hypothesis that a normalization of wall or media stress occurs during the process of tone development. The level of MT increased significantly as vessel size decreased. At 60 mmHg, vascular smooth muscle [Ca2+]i concentrations were similar in all vessels studied (averaging 230 ± 9.2 nM) and not correlated with vessel size or the extent of tone. Wall tension increased with increasing arterial size, but wall stress and media stress were similar in large versus small arteries. Media stress, in particular, was quite uniform in all vessels studied. Both morphological and calcium data support the concept of equalization of media stress (and, hence, vascular smooth muscle cell stress and force) as an underlying mechanism in determining the level of tone present in any particular vessel. The equalization of active (vascular smooth muscle cell) stress may thus explain differences in MT observed in the different-sized vessels constituting the arterial network and provide a link between arterial structure and function, in both short- and long-term (hypertension) pressure adaptation.

Voltage-gated K+ channels at an early stage of chronic hypoxia-induced pulmonary hypertension in newborn piglets

2006 ◽  
Vol 291 (6) ◽  
pp. L1169-L1176 ◽  
Author(s):  
Candice D. Fike ◽  
Mark R. Kaplowitz ◽  
Yongmei Zhang ◽  
Jane A. Madden
Keyword(s):  
Pulmonary Hypertension ◽  
Smooth Muscle ◽  
Cell Membrane ◽  
Smooth Muscle Cell ◽  
Muscle Cell ◽  
Chronic Hypoxia ◽  
Early Stage ◽  
Membrane Properties ◽  
Voltage Gated ◽  
Muscle Cell Membrane

Our purpose was to determine whether smooth muscle cell membrane properties are altered in small pulmonary arteries (SPA) of piglets at an early stage of pulmonary hypertension. Piglets were raised in either room air (control) or hypoxia for 3 days. A microelectrode technique was used to measure smooth muscle cell membrane potential ( Em) in cannulated, pressurized SPA (100- to 300-μm diameter). SPA responses to the voltage-gated K+ (KV) channel antagonist 4-aminopyridine (4-AP) and the KV1 family channel antagonist correolide were measured. Other SPA were used to assess amounts of KV1.2, KV1.5, and KV2.1 (immunoblot technique). Em was more positive in SPA of chronically hypoxic piglets than in SPA of comparable-age control piglets. The magnitude of constriction elicited by either 4-AP or correolide was diminished in SPA from hypoxic piglets. Abundances of KV1.2 were reduced, whereas abundances of both KV1.5 and KV2.1 were unaltered, in SPA from hypoxic piglets. At least partly because of reduced amounts of KV1.2, smooth muscle cell membrane properties are altered such that Em is depolarized and KV channel family function is impaired in SPA of piglets at an early stage of chronic hypoxia-induced pulmonary hypertension.

221. Localisation of relaxin receptors (Rxfp1) in the uterine artery and the effects of blocking circulating relaxin on passive mechanical wall properties in the uterine artery of late pregnant rats

2008 ◽  
Vol 20 (9) ◽  
pp. 21
Author(s):  
L. A. Vodstrcil ◽  
J. Novak ◽  
M. Tare ◽  
M. E. Wlodek ◽  
L. J. Parry
Keyword(s):  
Blood Flow ◽  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Uterine Artery ◽  
Late Pregnancy ◽  
Artery Wall ◽  
Pregnant Rats ◽  
Uterine Arteries ◽  
Wall Properties ◽  
Wall Stiffness

During pregnancy, the uteroplacental circulation undergoes dramatic alterations to allow for the large increase in blood flow to the feto-placental unit. These alterations are achieved through several mechanisms including structural changes in the uterine artery wall and endothelium-dependent vasodilation. Small renal arteries of relaxin-deficient mice and rats have enhanced myogenic reactivity and decreased passive compliance, and are relatively vasoconstricted (Novak et al. 2001, 2006). To date, no study has identified relaxin receptors (Rxfp1) in arteries or investigated the effects of relaxin deficiency in pregnancy on uterine artery function. The aims of this current study were to: 1) localise Rxfp1 in the uterine arteries, 2) measure myogenic reactivity in small uterine arteries after relaxin treatment, and 3) test the hypothesis that blocking circulating relaxin in late pregnancy will increase uterine artery wall stiffness. We demonstrated that Rxfp1 is expressed in the uterine arteries of pregnant mice and rats. Brightfield immunohistochemistry and immunofluorescence using antibodies specific for rat Rxfp1, α-smooth muscle actin and CD31 localised Rxfp1 protein predominantly to the vascular smooth muscle in the uterine artery of pregnant rats. Administration of recombinant human H2 relaxin (4 ug/h) for 6 h or 5 days in intact and ovariectomised rats reduced myogenic reactivity of small uterine arteries in vitro. Pregnant rats were treated with a monoclonal antibody against circulating relaxin (MCA1) or control (MCAF) for 3 days (Days 17–19) and uterine arteries were mounted on a pressure myograph to assess passive mechanical wall properties. Neutralising circulating relaxin in late pregnancy resulted in a significant increase in uterine artery wall stiffness. These data demonstrate that relaxin acts on the vascular smooth muscle cells in the uterine artery and may be involved in the pregnancy-specific vascular remodelling of uterine arteries to increase vasodilation and blood flow to the uterus and placenta. (1) Novak J et al. (2001). J Clin Invest 107: 1469–75 (2) Novak J et al. (2006). FASEB J 20: 2352–62

scholarly journals Inhibition of vascular smooth muscle inward-rectifier K+ channels restores myogenic tone in mouse urinary bladder arterioles

2017 ◽  
Vol 312 (5) ◽  
pp. F836-F847 ◽  
Author(s):  
Nathan R. Tykocki ◽  
Adrian D. Bonev ◽  
Thomas A. Longden ◽  
Thomas J. Heppner ◽  
Mark T. Nelson
Keyword(s):  
Blood Flow ◽  
Smooth Muscle ◽  
Urinary Bladder ◽  
Vascular Reactivity ◽  
Inward Rectifier ◽  
Intraluminal Pressure ◽  
Myogenic Tone ◽  
Vascular Beds ◽  
Oxide Synthase ◽  
Small Conductance

Prolonged decreases in urinary bladder blood flow are linked to overactive and underactive bladder pathologies. However, the mechanisms regulating bladder vascular reactivity are largely unknown. To investigate these mechanisms, we examined myogenic and vasoactive properties of mouse bladder feed arterioles (BFAs). Unlike similar-sized arterioles from other vascular beds, BFAs failed to constrict in response to increases in intraluminal pressure (5–80 mmHg). Consistent with this lack of myogenic tone, arteriolar smooth muscle cell membrane potential was hyperpolarized (−72.8 ± 1.4 mV) at 20 mmHg and unaffected by increasing pressure to 80 mmHg (−74.3 ± 2.2 mV). In contrast, BFAs constricted to the thromboxane analog U-46619 (100 nM), the adrenergic agonist phenylephrine (10 µM), and KCl (60 mM). Inhibition of nitric oxide synthase or intermediate- and small-conductance Ca2+-activated K+ channels did not alter arteriolar diameter, indicating that the dilated state of BFAs is not attributable to overactive endothelium-dependent dilatory influences. Myocytes isolated from BFAs exhibited BaCl2 (100 µM)-sensitive K+ currents consistent with strong inward-rectifier K+ (KIR) channels. Notably, block of these KIR channels “restored” pressure-induced constriction and membrane depolarization. This suggests that these channels, in part, account for hyperpolarization and associated absence of tone in BFAs. Furthermore, smooth muscle-specific knockout of KIR2.1 caused significant myogenic tone to develop at physiological pressures. This suggests that 1) the regulation of vascular tone in the bladder is independent of pressure, insofar as pressure-induced depolarizing conductances cannot overcome KIR2.1-mediated hyperpolarization; and 2) maintenance of bladder blood flow during bladder filling is likely controlled by neurohumoral influences.

scholarly journals Vasorelaxing effects of estetrol in rat arteries

2012 ◽  
Vol 215 (1) ◽  
pp. 97-106 ◽  
Author(s):  
Rob H P Hilgers ◽  
Suzanne Oparil ◽  
Wout Wouters ◽  
Herjan J T Coelingh Bennink
Keyword(s):  
Smooth Muscle ◽  
Smooth Muscle Cell ◽  
Muscle Cell ◽  
Soluble Guanylate Cyclase ◽  
Ex Vivo ◽  
Response Curves ◽  
Uterine Arteries ◽  
17Β Estradiol ◽  
Pharmacological Blockade ◽  
Relaxation Responses

This study comparedex vivorelaxing responses to the naturally occurring human hormone estetrol (E4) vs 17β-estradiol (E2) in eight different vascular beds. Arteries were mounted in a myograph, contracted with either phenylephrine or serotonin, and cumulative concentration-response curves (CRCs) to E4and E2(0.1–100 μmol/l) were constructed. In all arteries tested, E4had lower potency than E2, although the differential effect was less in larger than smaller arteries. In uterine arteries, the nonselective estrogen receptor (ER) blocker ICI 182 780 (1 μmol/l) caused a significant rightward shift in the CRC to both E4and E2, indicating that the relaxation responses were ER dependent. Pharmacological blockade of nitric oxide (NO) synthases byNω-nitro-l-arginine methyl ester (l-NAME) blunted E2-mediated but not E4-mediated relaxing responses, while inhibition of prostaglandins and endothelium-dependent hyperpolarization did not alter relaxation to either E4or E2in uterine arteries. Combined blockade of NO release and action withl-NAME and the soluble guanylate cyclase (sGC) inhibitor ODQ resulted in greater inhibition of the relaxation response to E4compared with E2in uterine arteries. Endothelium denudation inhibited responses to both E4and E2, while E4and E2concentration-dependently blocked smooth muscle cell Ca2+entry in K+-depolarized and Ca2+-depleted uterine arteries. In conclusion, E4relaxes precontracted rat arteries in an artery-specific fashion. In uterine arteries, E4-induced relaxations are partially mediated via an endothelium-dependent mechanism involving ERs, sGC, and inhibition of smooth muscle cell Ca2+entry, but not NO synthases or endothelium-dependent hyperpolarization.

Abstract 488: Arteriolar Smooth Muscle Calcium Waves Depend on Calcium Influx through Voltage-gated Calcium Channels

Hypertension ◽  
2012 ◽  
Vol 60 (suppl_1) ◽  
Author(s):  
William F Jackson ◽  
Erika B Westcott
Keyword(s):  
Smooth Muscle ◽  
Striated Muscle ◽  
Calcium Influx ◽  
Ryanodine Receptors ◽  
Myogenic Tone ◽  
Voltage Gated ◽  
Voltage Gated Calcium Channels ◽  
Bayk 8644 ◽  
Muscle Calcium ◽  
Arteriolar Diameter

Smooth muscle cells (SMCs) in arterioles from striated muscle display IP 3 receptor-dependent Ca 2+ waves that contribute to global myoplasmic Ca 2+ concentration and myogenic tone. However, the contribution of voltage-gated Ca 2+ channels (VGCC) to these arteriolar Ca 2+ signals is unknown. We tested the hypothesis that Ca 2+ waves depend on Ca 2+ influx through VGCC in cremaster muscle arterioles loaded with Fluo-4 and imaged by confocal microscopy. At rest, with vessels pressurized to 80 cm H 2 O in 2 mM Ca 2+ , arteriolar diameter was 28 ± 2 μm (n = 5), and SMCs displayed Ca 2+ waves with frequency (FREQ) = 0.21 ± 0.06 Hz, occurrence (OCC) = 3.5 ± 1.0 waves/SMC and amplitude (AMP) = 1.7 ± 0.1 F/Fo. Removal of extracellular Ca 2+ dilated the arterioles to 39 ± 1 μm, and inhibited Ca 2+ waves (FREQ = 0.1 ± 0.03, OCC = 1.7 ± 0.5 waves/SMC and AMP = 1.4 ± 0.06 F/Fo; p < 0.05 vs. rest) indicating that Ca 2+ waves depended, in part, on influx of extracellular Ca 2+ . Similarly, the VGCC antagonist, nifedipine (1 μM), dilated the arterioles to 34 ± 1.3 μm and also inhibited Ca 2+ waves (FREQ = 0.07 ± 0.02 Hz, OCC = 1.1 ± 0.5 waves/SMC, AMP = 1.4 ± 0.05 F/Fo; p < 0.05 vs. rest). Hyperpolarization of SMCs with the K + channel agonist, cromakalim (10 μM), dilated arterioles from 49 ± 3 to 59 ± 4 μm (n = 4, p < 0.05) and also reduced Ca 2+ wave FREQ (0.1 ± 0.04 to 0.03 ± 0.003 Hz), OCC (1.7 ± 0.04 to 0.5 ± 0.05 waves/SMC) and AMP (1.5 ± 0.04 to 1.2 ± 0.004 F/Fo) (p < 0.05). Conversely, depolarization of SMCs with the BK Ca channel blocker, TEA (1 mM), constricted arterioles from 28 ± 2 to 16 ± 1 μm (n = 5, p < 0.05) and increased wave FREQ (0.2 ± 0.1 to 0.5 ± 0.1 Hz, p < 0.05) and OCC (4 ± 1 to 8 ± 2 waves/SMC, p < 0.05), effects blocked by nifedipine (1μM) (p < 0.05). Similarly, in arterioles pressurized to 20 cm H 2 O to eliminate myogenic tone and reduce basal VGCC activity, application of the VGCC agonist, BayK 8644 (5 nM) constricted the arterioles from 14 ± 1 to 8 ± 1 μm and increased wave FREQ (0.2 ± 0.1 to 0.6 ± 0.1 Hz) and OCC (3 ± 1 to 10 ± 1 waves/SMC) (n = 6; p < 0.05), effects that were independent of ryanodine receptors, as Ca 2+ waves were unaffected by ryanodine (50 μM) in the absence or presence of BayK 8644 (n = 6; p > 0.05). These data support the hypothesis that Ca 2+ waves in arteriolar SMCs depend, in part, on Ca 2+ influx through VGCC.

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